A role for p53 in the β-amyloid-mediated regulation of the lysosomal system

Marie P. Fogarty, Róisín M. McCormack, Janis Noonan, Declan Murphy, Aoife Gowran, Veronica A. Campbell

Research output: Contribution to journalArticle

Abstract

β-Amyloid accumulates around neurons in Alzheimer's disease and is thought to contribute to the neurodegenerative process. This study examined the role of the tumour suppressor protein, p53, in the neurodegenerative pathway, with focus on the interaction of p53 with the lysosomal system β-Amyloid increased expression of p53 and its transcription target, Bax, in cultured cortical neurons. In addition, Aβ increased the association of phospho-p53ser15 with the lysosomal compartment and this correlated with destabilization of the lysosomal membrane and a concomitant increase in cytosolic cathepsin-L activity. These effects of β-amyloid were abolished by the p53 inhibitor, pifithrin-α, and siRNA-mediated knockdown of p53, demonstrating that p53 is a critical regulator of lysosomal integrity and the induction of cathepsin-L protease activity. In addition, activation of the apoptotic cascade was abolished by pifithrin-α. We conclude that p53 associates with the lysosome to regulate a lysosomal branch of the apoptotic cascade which contributes to β-amyloid-mediated neurodegeneration.

Original languageEnglish
Pages (from-to)1774-1786
Number of pages13
JournalNeurobiology of Aging
Volume31
Issue number10
DOIs
Publication statusPublished - Oct 2010

Keywords

  • β-Amyloid
  • Apoptosis
  • Lysosome
  • P53

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

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